Antibody therapy for cancer often involves the use of antibodies, or antibody fragments, against a tumor antigen to target antigen-expressing cells. Antibodies, or antibody fragments, may have direct or indirect cytotoxic effects on cancer cells. Direct effects include the induction of apoptosis, the blocking of growth factor receptors, and anti-idiotype antibody formation. Indirect effects include antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-mediated cellular cytotoxicity (CDC). When conjugated or fused to cytotoxic moieties, the antibodies, or fragments thereof, provide a method of targeting the cytotoxic moiety towards the tumor antigen-expressing cells (Green, et al., Cancer Treatment Reviews, 26:269-286 (2000)).
Because antibody therapy typically targets cells expressing a particular antigen, there is a possibility of cross-reactivity with those normal cells or tissues that express the same or a highly similar antigen. Although some cells, such as hematopoietic cells, are readily regenerated, cross-reactivity with many non-cancerous cells or tissues can lead to detrimental results. Thus, considerable research has focused on identifying tumor-specific antigens. Such antigens are found almost exclusively on tumors or are expressed at a greater level in tumor cells than the corresponding normal tissue. Tumor-specific antigens provide targets for anti-cancer therapies. Antibodies specific to such tumor-specific antigens can be conjugated to cytotoxic compounds or can be used alone in immunotherapy. Immunotoxins target cytotoxic compounds to induce cell death. For example, anti-CD22 antibodies conjugated to deglycosylated ricin A may be used for treatment of B cell lymphoma that has relapsed after conventional therapy (Amlot, et al., Blood 82:2624-2633 (1993)).
Immunotherapy provides a method of harnessing the immune system to treat various pathological states, such as cancer, autoimmune disease, transplant rejection, hyperproliferative conditions, inflammatory diseases, and allergic reactions. The immune system functions to eliminate organisms or cells that are recognized as non-self, including microorganisms, neoplasms and transplants. A cell-mediated host response to tumors includes the concept of immunologic surveillance, by which cellular mechanisms associated with cell-mediated immunity, destroy newly transformed tumor cells after recognizing tumor-associated antigens (i.e., antigens associated with tumor cells that are not apparent on normal cells). Furthermore, a humoral response to tumor-associated antigens enables destruction of tumor cells through immunological processes triggered by the binding of an antibody to the surface of a cell, such as ADCC and CDC.
Recognition of an antigen by the immune system can trigger a cascade of events including cytokine production, B-cell proliferation, and subsequent antibody production. Often tumor cells have reduced capability of presenting antigen to effector cells, thus impeding the immune response against a tumor-specific antigen. In some instances, the tumor-specific antigen may not be recognized as non-self by the immune system, preventing an immune response against the tumor-specific antigen from occurring. In such instances, stimulation or manipulation of the immune system provides effective techniques of treating cancers expressing one or more tumor-specific antigens.
For example, rituximab (RITUXAN®, Biogen DEC, Inc., Cambridge, Mass., USA) is a chimeric antibody directed against CD20, a B cell-specific surface molecule found on >95% of B-cell non-Hodgkin's lymphoma (Press, et al., Blood 69:584-591 (1987); Malony, et al., Blood 90: 2188 (1997)). Rituximab induces ADCC and inhibits cell proliferation through apoptosis in malignant B cells in vitro (Maloney, et al., Blood 88 637a (1996)). Rituximab is currently used as a therapy for advanced stage or relapsed low-grade non-Hodgkin's lymphoma, which has not responded to conventional therapy.
MYLOTARG® (Wyeth, N.J.; gentuzumab ozogamicin), a chimeric antibody directed against CD33, is an example of an alternative targeted antibody therapy. In this case, the antibody is conjugated to a cytotoxic molecule, calicheamicin. Thus, when the antibody binds to the target cell and is internalized, the cytotoxic molecule kills the cells. MYLOTARG® is currently used as a therapy for patients over the age of 60 with relapsed acute myelogenous leukemia who are not considered candidates for standard chemotherapy.
Several cell surface receptors are predominantly expressed in hematologic malignancies, such as leukemias and lymphomas. Some of these molecules belong to the C-type lectin-like family which is involved in processes such as regulation of cell proliferation. One such member of the C-type lectin-like family, CLL-1, is a cell surface glycoprotein whose expression is restricted to myeloid cells and may have a role in regulating myeloid cell proliferation and differentiation (Bakker et al., Cancer Res. 64:8443-8450 (2004); Marshall et al., J. Biol. Chem. 279:14792-14802 (2004)).
The currently available therapies for hematologic malignancies carry adverse and often severe side effects. For example, complications arising from MYLOTARG® administration include hepatotoxicity, veno-occlusive disease, severe myelosuppression (in ˜98% of patients), tumor lysis syndrome, immune hypersensitivity syndrome and respiratory disorders. Thus, there is a need to identify new therapies for hematologic malignancies that are efficacious with reduced side effects. Since CLL-1 is selectively expressed on myeloid cells, compositions that recognize and bind to CLL-1 may be useful for such therapies of hematogic malignanices, especially those of myeloid origin.